Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the role of small amounts of DHT in prostate tissue as a stimulus to epithelial cell growth (protein synthesis) we studied tissue from patients given various androgen-blocking drugs prior to transurethral resection of the prostate (TURP) and measured epithelial protein synthesis and DHT in the tissue specimens. We also studied the effects on stromal cell protein synthesis of an antiestrogen, tamoxifen. Test drugs prior to TURP included Megace 160 mg per day, Megace 160 mg per day plus Tamoxifen 40 mg per day, Megace 160 mg a day plus ketoconazole 1200 mg per day and tamoxifen 40 mg/day. The tissue was processed immediately and epithelial and stromal cells separated by digestion of tissue with 0.5% collagenase. After separation, epithelial cells were labeled with either [3H]leucine or L-[35S]methionine. Stromal cells were labelled with [3H]proline. DHT was measured in whole prostate tissue. Megace alone and Megace plus tamoxifen significantly decreased both [3H]leucine incorporation into protein and tissue concentration of DHT; Megace plus ketoconazole significantly decreased L-[35S]methionine incorporation into protein and DHT. Tamoxifen significantly decreased stromal protein synthesis. When the data correlating DHT with epithelial protein synthesis using both labeling techniques were combined, the curves were parallel and a strong correlation was noted between DHT and protein synthesis over a wide range of values (P less than 0.001). These results suggest that in hormone-dependent prostate cancer even small amounts of prostate DHT such as may occur from adrenal androgens following castration may significantly stimulate growth of the tumor epithelial cells. Since tamoxifen decreased stromal protein synthesis, estrogen is likely a significant growth stimulus to the increased stromal mass characteristic of benign prostatic hypertrophy.
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PMID:Effect of antiandrogen and/or antiestrogen blockade on human prostate epithelial and stromal cell protein synthesis. 243 6

To evaluate the role of small amounts of prostatic tissue dihydrotestosterone (DHT) as a stimulus to epithelial cell protein synthesis, we studied tissue from 27 patients given various androgen-blocking drugs for 1 week before transurethral resection of the prostate (TURP) and measured epithelial protein synthesis and DHT levels in the tissue specimens. Test drugs before TURP included megestrol acetate 160 mg per day, with and without Tamoxifen 40 mg per day, or ketoconazole 1200 mg per day. The tissue was processed immediately and epithelial cells separated by digestion of tissue with 0.5% collagenase. After separation, epithelial cells were labelled with either 3H-leucine or L-35S-methionine. The DHT level was measured in whole prostatic tissue. Megestrol acetate alone and with tamoxifen significantly decreased both the incorporation of 3H-leucine into protein and the tissue concentration of DHT; megestrol acetate plus ketoconazole significantly decreased L-35S-methionine incorporation into protein and the DHT level. When the data correlating DHT with protein synthesis using both labelling techniques were combined, the curves were parallel and a strong correlation was noted between DHT and protein synthesis over a wide range of values (P less than 0.001). These results suggest that in hormone-dependent prostatic cancer even small amounts of prostatic DHT such as may occur from adrenal androgens following castration may significantly stimulate protein synthesis of the tumour epithelial cells.
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PMID:Relationship between human prostatic epithelial cell protein synthesis and tissue dihydrotestosterone level. 366 14

The effect of tamoxifen on Ca(2+) signaling and viability in Madin Darby canine kidney (MDCK) cells was investigated by using fura-2 as a Ca(2+) probe. Tamoxifen evoked a rise in cytosolic free Ca(2+) levels ([Ca(2+)](i)) concentration-dependently between 1 and 50 microM with an EC50 of 10 microM. The response was decreased by extracellular Ca(2+) removal. In Ca(2+)-free medium, pretreatment with 5 microM tamoxifen abolished the [Ca(2+)](i) increase induced by the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (1 microM), but pretreatment with brefeldin A (50 microM; a Ca(2+) mobilizer of the Golgi complex), thapsigargin (an inhibitor of the endoplasmic reticulum Ca(2+) pump), and carbonylcyanide m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler), only partly inhibited tamoxifen-induced [Ca(2+)](i) increases. This suggests that tamoxifen released Ca(2+) from multiple pools. Addition of 3 mM Ca(2+) induced a [Ca(2+)](i) rise after pretreatment with 5 microM tamoxifen in Ca(2+)-free medium. Inhibiting inositol 1,4,5-trisphosphate formation with the phospholipase C inhibitor U73122 (2 microM) did not alter 5 microM tamoxifen-induced Ca(2+) release. The [Ca(2+)](i) increase induced by 5 microM tamoxifen was not altered by La(3+), nifedipine, verapamil, or diltiazem. Tamoxifen (1-10 microM) decreased cell viability in a concentration- and time-dependent manner. Tamoxifen (5 microM) also increased [Ca(2+)](i) in neutrophils, bladder cancer cells, and prostate cancer cells from humans and glioma cells from rats. Collectively, it was found that tamoxifen increased [Ca(2+)](i) in MDCK cells by releasing Ca(2+) from multiple Ca(2+) stores in a manner independent of the production of inositol 1,4, 5-trisphosphate and also by triggering Ca(2+) influx from extracellular space. The [Ca(2+)](i) increase was accompanied by cytotoxicity.
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PMID:Dual effect of tamoxifen, an anti-breast-cancer drug, on intracellular Ca(2+) and cytotoxicity in intact cells. 1100 Jan

Female hormones, especially estrogens, play an important role in the pathogenesis of breast neoplasms and are a principal determinant of their biological behavior. Endocrine manipulation through medical or surgical means can often lead to objective shrinkage of breast tumors. Tamoxifen, a triphenylethylene estrogen receptor modulator, is currently the most widely used hormonal treatment for breast cancer. It has been conclusively demonstrated to reduce the risk of relapse following definitive local therapy (and systemic chemotherapy, when indicated) of invasive or noninvasive breast cancer. Recently, it has also been shown to reduce the incidence of breast cancer in healthy women who are at high risk of developing the disease. In addition, it can prevent osteoporosis and reduce the risk of fractures in postmenopausal women. However, its use is also complicated by an increased incidence of endometrial hyperplasia/carcinoma, venous thromboembolism, cataracts, and in some cases, emergence of tamoxifen-dependent clones of breast cancer. These side effects (except cataracts) are believed to be related to estrogen-agonist effects of tamoxifen. Newer drugs, which are "pure antiestrogens" or inhibitors of estrogen biosynthesis, are devoid of such estrogen-agonist activity and may not have the liability of many of these side effects. However, these agents would also be expected to lack the potentially beneficial effects of tamoxifen on lipids and skeletal system. The ability of tamoxifen to act as an estrogen-agonist or estrogen-antagonist in a tissue-specific fashion has led to the concept of selective estrogen-receptor modulation. Selective estrogen receptor modulators (SERMs), which are devoid of estrogen-agonist effects on the uterus or breast cancer cells but retain potentially beneficial effects on bones and lipids, have been described as "ideal" SERMs. A number of such compounds are currently being tested. Raloxifene is already approved for prevention of osteoporosis and has potential efficacy for prevention and treatment of breast cancer. An analogue of raloxifene, LY353381, is currently in Phase II clinical trials for treatment of breast cancer, with promising early results. EM800 and CP336156 are other promising ideal SERMs in clinical trials. These compounds may provide better treatment and chemoprevention alternatives for breast cancer as compared to tamoxifen, aromatase inhibitors, and pure antiestrogens. In addition, they may also prove to be useful for the treatment and prevention of prostate cancer as well as for treating benign gynecological diseases such as fibroids and endometriosis. Future laboratory efforts should focus on further broadening the efficacy profile of SERMs (e.g., prevention of Alzheimer's disease and elevation of high-density lipoproteins to improve the likelihood of cardiovascular benefit) and narrowing their side-effect profile (e.g., risk of thromboembolism and hot flashes).
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PMID:Selective estrogen receptor modulation: the search for an ideal hormonal therapy for breast cancer. 1148 8

Androgen ablation therapy induces apoptosis only in androgen-sensitive prostate cancer cells; therefore, other cytotoxic drugs are being used to induce apoptosis in androgen-refractory cells. Mifepristone, an antiprogestin used individually or together with the antiestrogen Tamoxifen, has been recommended for induction of cell death and treatment of several hormonal cancers. However, little is known about the mechanism of action of these drugs in prostate cancer. Therefore, we investigated the effect of Mifepristone on the tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) pathway, a newly identified and very effective member of tumor necrosis factor-alpha family. Mifepristone and Tamoxifen induced significant expression of death receptors in prostate cancer cells in vitro and in xenografts. However, Mifepristone in combination with Tamoxifen did not increase prostate cancer cell death compared with their individual values. The involvement of the TRAIL pathway was further confirmed by the activation of caspase-8 in Mifepristone-treated cells. This was followed by truncation of Bid, confirming that Mifepristone activates the TRAIL pathway. This knowledge is being used to design a combination treatment of TRAIL and Mifepristone to induce significant apoptosis in prostate cancer cells.
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PMID:Differential expression of members of the tumor necrosis factor alpha-related apoptosis-inducing ligand pathway in prostate cancer cells. 1158 52

Successful therapy should induce apoptosis in prostate cancer cells irrespective of their androgen response. We have investigated the possibility of utilizing Mifepristone and Tamoxifen as treatment options for prostate cancer cells. Because preliminary results demonstrated induction of apoptosis by these drugs, the mechanism of induction of apoptosis was investigated. LNCaP-C4 prostate cancer cells were treated with Mifepristone and/or Tamoxifen. To confirm cytotoxic effects, nude mice with LNCaP-C4 xenografts were treated with Mifepristone and Tamoxifen. Cell viability was assayed using Sulforhodamine B (SRB) assay and DNA fragmentation was measured by ELISA. Culture media from vehicle- and drug-treated cells were collected and secretion of transforming growth factor beta1 (TGFbeta1) was estimated by ELISA. Role of TGFbeta1 was confirmed by inhibiting its function using TGFbeta1 antibody or M6P, which blocked activation of TGFbeta1. Apoptotic effects were determined by immunoblots of cytochrome c levels in cytosol and by in vitro colorimetric assay of caspase-3 activity. Results showed that although both drugs induced apoptosis in LNCaP-C4 cells, Mifepristone was more effective. The effects of these drugs on xenografts confirmed in vitro results. It was hypothesized that drug-induced secretion of TGFbeta1 may be responsible for induction of apoptosis. Neutralization of TGFbeta1 with an antibody or blocking the activation of TGFbeta1 by M6P abrogated the effects of Mifepristone and Tamoxifen confirming our hypothesis. Furthermore, treatment with Mifepristone and/or Tamoxifen released cytochrome c into the cytoplasm and induced activity of caspase-3, providing evidence that the drug-stimulated secretion of TGFbeta1 was responsible for induction of apoptosis in these cells. In conclusion, both Mifepristone and Tamoxifen induced apoptosis mediated through TGFbeta1. However, no critical advantage was noted by the addition of Tamoxifen to Mifepristone treatment.
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PMID:Mifepristone-induced secretion of transforming growth factor beta1-induced apoptosis in prostate cancer cells. 1242 76

Breast and prostate cancers are the two predominant hormone-responsive tumours. The use of the antioestrogen tamoxifen in the treatment of breast cancer has evolved over the past 30 y from treatment for advanced breast cancer to prevention. Tamoxifen is currently the endocrine treatment of choice for advanced breast cancer and for adjuvant therapy in a broad spectrum of women whose primary tumours have functional oestrogen receptors. It has also been shown to reduce the incidence of breast cancer in high-risk women. Non-steroidal antiandrogen therapy is used in the treatment of prostate cancer, but its role is still being defined. The clinical development of tamoxifen and that of the antiandrogens are reviewed and parallels are uncovered which provide insight into contemporary and future management of hormone-responsive prostate cancer.Prostate Cancer and Prostatic Diseases (2001) 4, 72-80
Prostate Cancer Prostatic Dis 2001
PMID:Will the experience with tamoxifen in breast cancer help define the role of antiandrogens in prostate cancer? 1249 42

In this phase I/II clinical trial the antitumor activity of high-dose tamoxifen when administered in combination with vinblastine was assessed and the toxicity profile of this combination characterized. All 25 patients enrolled in this study were required to have androgen-independent prostate cancer and to maintain androgen ablation during treatment. Vinblastine was given by continuous infusion over 5 days. Doses were increased from 0.9 mg/m2/day to 1.5 mg/m2/day in successive cohorts of at least 3 patients, with no further escalation even in the absence of dose-limiting toxicity. Intra-patient dose escalation was permitted. Tamoxifen was administered at a dose of 200 mg/kg on day 1, then 120 mg/kg/day on day 2. Standard response criteria were utilized to assess antitumor activity and CTC toxicity criteria were used. Quality of life (QOL) pain assessments were evaluated at each visit to the clinic. Most patients tolerated the highest dose of vinblastine at 1.5 mg/m2/day by continuous infusion over 5 days with 200 mg/kg/day of tamoxifen on day 1 and day 2. One patient had a greater than 50% decline in prostate-specific antigen that lasted for 170 days. Two patients received dose reductions because of toxicity. The most common serious toxicities included neutropenia, and fatigue. Reversible neurosensory, neuromotor, neurocortical and neurocerebellar toxicities were reported. Six of the 25 patients enrolled in the study (24%) experienced reversible neurologic toxicity of at least grade III. No statistically significant differences between precycle assessment of QOL and subsequent cycles were observed. It is concluded that vinblastine at 1.5 mg/m2/day continuous i.v. infusion combined with tamoxifen 200 mg/kg/day on day 1 and day 2 is inactive, and not without toxicity in the treatment of advanced metastatic androgen-independent prostate cancer.
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PMID:A phase I/II study of high-dose tamoxifen in combination with vinblastine in patients with androgen-independent prostate cancer. 1285 95

Microsomal cytochrome P450 (CYP 450) enzyme aromatase belongs to CYP 19 super family. It is involved in the conversion of androgens to estrogens. In postmenopausal women the main sites of aromatisation are skin, adipose tissue and breast. Aromatase localized in breast tumor produces sufficient estrogen for its proliferation. Hence it is an important target for the treatment of hormone dependent breast cancer in postmenopausal women. There are mainly two types of aromatase inhibitors, one is steroidal another is nonsteroidal type. The first and second generation aromatase inhibitors encounter the undesirable drug- drug interactions besides being not very specific and plagued with pharmacokinetic problems. Third generation aromatase inhibitors developed recently are more potent and specific with a greater capacity to annihilate circulating estrogen levels. These agents have satisfactory pharmacokinetic profiles and are devoid of major drug-drug interactions. Third generation aromatase inhibitors became drugs of choice for both first and second line treatment of advanced breast cancer. Aromatase inhibitors can also be used for neoadjuvant therapy of breast cancer in which they have achieved better therapeutic efficacy than tamoxifen. Early results of ATAC (Armidex Tamoxifen Alone or Combination) trial suggest that anastrozole is superior to tamoxifen in adjuvant setting for disease free survival, particularly in receptor positive patients, and in reducing the incidence of contralateral breast cancer. Therapeutic potential of aromatase inhibitors stretches beyond the postmenopausal breast cancer treatment as they also play a role in the treatment of estrogen dependent benign and malignant conditions such as gynaecomastia, prostate cancer, fibroadenomata and the induction of ovulation. By virtue of their ability to reduce estrogen levels they pose problems like demineralization of bone, hot flushes and anti-implantation effects.
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PMID:Aromatase inhibitors: a new paradigm in breast cancer treatment. 1557 17

A randomized, double-blind, placebo-controlled multicenter trial involving 107 men receiving bicalutamide ('Casodex') 150 mg/day therapy following radical therapy for prostate cancer assessed tamoxifen ('Nolvadex') 20 mg/day and anastrozole ('Arimidex') 1 mg/day for the prophylaxis and treatment of gynecomastia/breast pain. Tamoxifen, but not anastrozole, significantly reduced the incidence of gynecomastia/breast pain when used prophylactically and therapeutically. Serum testosterone levels increased with tamoxifen relative to placebo but prostate-specific antigen levels declined in all treatment groups. Further studies are needed to define the optimum tamoxifen dose and to assess any impact on cancer control. The use of tamoxifen in this setting remains to be investigated.
Prostate Cancer Prostatic Dis 2005
PMID:Prevention and management of bicalutamide-induced gynecomastia and breast pain: randomized endocrinologic and clinical studies with tamoxifen and anastrozole. 1568 54


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